chr2-151669043-G-T

Position:

• chr2-151669043-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001164507.2(NEB):​c.4595C>A​(p.Ala1532Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,440,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1532T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.4595C>A	p.Ala1532Asp	missense_variant	39/182	ENST00000427231.7
NEB	NM_001164508.2	c.4595C>A	p.Ala1532Asp	missense_variant	39/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.4595C>A	p.Ala1532Asp	missense_variant	39/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.4595C>A	p.Ala1532Asp	missense_variant	39/182	5	NM_001164507.2	A2
NEB	ENST00000409198.5	c.4595C>A	p.Ala1532Asp	missense_variant	39/150	5
NEB	ENST00000484968.1	n.447C>A		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1440610 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 714712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000364

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nemaline myopathy 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2021

This sequence change replaces alanine with aspartic acid at codon 1532 of the NEB protein (p.Ala1532Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NEB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;.;T;.;T;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;T;D;D;.;.
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.2	M;M;.;M;M;M;M
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.9	D;D;.;D;D;.;.
REVEL	Uncertain	0.49
Sift	Uncertain	0.011	D;D;.;D;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.99	.;.;.;.;D;.;.
Vest4		0.79
MutPred		0.73		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.82
MPC		0.31
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.64
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1456966310; hg19: chr2-152525557;